Mi Kieu Bui
Drexel Undergraduate
December, 8, 2012
Abstract
Leukemia is a broad class of blood cancer that can be further categorized into four major classes, each with their own subtypes based on a number of morphological and cytological differences. There is no exact cause of leukemia but some people have a higher risk for the development of the disease than others due to a complex combination of many factors that may be environmentally or genetically based. Leukemia was first described over 200 years ago but it was not until less than 100 years ago that any significant advances or methods of treatments are formed. Leukemia, while not exactly curable, can be treated in a number of different ways. All of these treatment options have their own advantages and disadvantages and are usually specific to each patient depending on many individual characteristics of the patients and the disease.
Introduction
Leukemia is a class of blood cancer that results from a characteristic overabundance of white blood cells. Not to be confused with lymphoma, which contains white blood cells generated by the lymphoid immune system; leukemia generally refers to the white blood cells generated by the bone marrow [1]. In standard leukemia, blood white cells, either myelocytes or lymphocytes, rapidly and uncontrollably proliferate and accumulate in the blood stream which generates an overabundance of the white blood cells and suppresses the production of other components of blood such as red blood cells, platelets, and various antibodies; this results in a weakened immune system. The suppression is what resulted in symptoms commonly associated with leukemia patients such as fatigue, shortness of breath, fever, chills, migraines, bone or joint pain, excessive bleeding and bruising, and infections [2]. Left untreated, leukemia commonly results in death, with differing life expectancies depending on the subtype of leukemia. Leukemia is divided into four major subtypes which can also be further differentiated based on genetic aberrations. The four major subtypes of leukemia are distinguished based on a number of morphological differences that concern the type of white blood cells affected and their maturation stages. The four subtypes are chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and acute lymphocytic leukemia (ALL) [3]. Myeloid (or myelogenous) and lymphocytic leukemia refer to the cell types in which this disorder develop and acute or chronic are classified based on the maturity of these cells. In chronic leukemia, the cells are mature and thus divide more slowly than its acute counterpart, which refers to young white blood cells called blasts which divide much more frequently. Acute leukemia frequently occurs quite suddenly while chronic has a slower onset. Acute leukemia, with the exception of AML, is more commonly diagnosed in young children while older patients typically suffer from chronic leukemia [4].
Causes and Risk Factors
There are no truly known causes and risk factors for most types of leukemia; however, there are suspected risk factors. Risk factors can include exposure to radiation, exposure to carcinogenic chemicals, viral infections, genetic predisposition, or chromosomal abnormality such as Down syndrome [5].
When various types of radiation were first discovered before the start of the 19th century by numerous people, including Rutherford, Edison, and others, it became a frequent and flippant method of commercial use and diagnostic processes. Radium or thorium based products were released over-the-counter and consumed by the general public, many physicians used radiation therapy as an attempted method to cure diseases, and many of the general public employed flippant use of x-rays for pointless entertainment. It was not until years later and many linked cases of leukemia and various other cancers arising from people with high levels of exposure to radiation that the dangers of radiation were truly known or accepted. Other information supporting the fact that radiation is linked to leukemia came from atomic bomb survivors from the Japan detonation of the atomic bombs and from workers in the area after the events. More studies that supports the danger of radiation came from workers with inadequate protective equipments in nuclear power plants [6].
Radiation induces leukemia or other cancer by directly damaging the DNA through two possible mechanisms. The first of which is the direct ionization of water which produces highly reactive radicals and the second mechanism is the direct damage to DNA caused by outer shell electrons that are knocked off during radiation exposure. Both of these mechanisms can cause single-strand breaks or double-strand breaks in the DNA which may result in unstable chromosomes and lead to various mutations. Some chromosomal rearrangements may activate certain protooncogenes that can lead to the development of leukemia. Any mutation that occurs in a cell is most likely to transfer into its entire offspring as shown in Figure 1. There is a linear relationship between the dosage of radiation and the number of mutations that arises as shown in Figure 2, indicating that higher level of radiation exposure lead to a higher risk of leukemia. However, other factors and phenomena may complicate the understanding of radiation induced leukemia [6].
Figure 1: Schematic representation of radiation-induced genomic instability [7]
Figure 2: Dose-response graph for the induction of mutations [7]
Leukemia can also be caused by viral infections such as by the HTLV-I (human T-lymphotropic virus type I. Viruses generally infect cells by entering the host’s cellular environment and injecting viral DNA or RNA, which typically alters the host’s own mechanisms into a viral production industry. For effective infections, there has to be a balance between the host immunity and viral virulence since it is not advantageous to have the virus or the host killed too soon. How this actually occurs is still unclear in immunobiology [8]. As shown in Figure 3, there are various points that can lead to what constitutes as an acute or chronic infection as well as for maintaining the infection. In the case of the HTLV-I infection, the virus may be transmitted through sexual intercourse, from mother to child via breast-feeding, or via intravenous exposure to blood [9].
Figure 3: Mechanism of viral infection [8]
HTLV-1 is linked to the development of ATL (Adult T-cell Leukemia) which may occur when the virus infect lymphocytes in the bone marrow [9].
The risk for leukemia can also be caused by genetic predisposition which occurred since specific mutations can be inherited in a Mendelian fashion which may manifest in a favorable environment. Some studies show that leukemia can be caused by random sporadic mutations; however, there is increasing evidence that the risk for leukemia runs in family based on a variety of studies. The search for a single chromosome or gene that indicates a high risk for leukemia is still futile; however, several locations on the genome have been identified as most likely. CLL is most commonly found to be inherited and appears to be located on a single gene that is based on the typical autosomal dominant inheritance. With various complications of expressed phenotypes and environmental conditions, it is difficult to localize the exact location on the chromosome. AML on the other hand, is also shown to be frequently a familiar predisposition which may be inherited from a form of platelet disorder and is found to most frequently occur in patients with a certain mutated protein [10].
Other risks of leukemia associated with inherited genetic disorders are in patients with Down Syndrome and bone marrow failure syndromes [10]. Notice that patients diagnosed with these chromosomal disorders are not guaranteed to develop leukemia but are merely at a higher risk of developing leukemia.
History of Early Treatments
The first known case of leukemia was discovered by Peter Cullen in the early 1800s when he examined a patient and noticed the appearance of a milky serum in the blood. The next few cases of leukemia have differing symptoms but similar appearances in the composition of blood. It was not until 1845 that the name leukemia, meaning white blood in Greek, was coined by John Hughes Bennett. After many years of various contributions by different physicians, the disease was finally connected to the bone marrow in the late 1800s [3].
When leukemia was first described, treatment options were not exactly available and acting physicians back then tended to treat patients based on their displayed symptoms. The most common treatment was blood-letting in which patients seemed to recover but it was not documented as to how long they survived after the treatment. It was not until more than 100 years later that any alternative treatment options were created. The first of which were iron supplements in the 1930s which only appeared to work because it treated the anemia symptoms commonly associated with not having enough oxygen carried by the red blood cells. After that, various radiation techniques were used including exposure to radioactive compounds or administration of electromagnetic rays [3]. These techniques may merely kill the cancerous cells at the moment but they also harmed the body to a significant degree and caused a higher risk for the reoccurrences of leukemia or other types of cancer.
Current Treatments
Roughly 200 years after leukemia was first documented, treatment options have significantly improved by leaps and bounds to the point that cures are actually available for certain types of leukemia. Current options for treatment are chemotherapy, immunotherapy, radiation therapy, and transplant. Each of these treatment options has their own advantages and disadvantages and the treatment plan utilized for each patient is unique and may involve one or a combination these options. The treatment plans for patients are generated with the types and subtypes of leukemia, age, health issues, and various other criteria and factors in mind. Most leukemia are initially diagnosed via a bone marrow biopsy which lead to very specific classifications of the subtypes of the disease.
Chemotherapy drugs can be administered orally or by injection into the veins. The goal of chemotherapy or drug therapy is to kill the cancerous cells and hopefully induce remission. However, the general problem with this is that it is quite difficult to synthesize drugs that are specific enough to attack and kill the leukemia cells without harming the body’s own regular functioning cells. Added to this complication is the fact that not enough is actually understood regarding the mechanism of leukemia and how to differ between normal and abnormal white blood cells. Another complication is the developing drug resistance that the cancerous cells seemed to adopt as they adapt to various drugs.
For the chronic subtypes of leukemia, the drug therapy is not as intensive as the acute types because chronic leukemia develop much more slowly and can usually be controlled by periodic drug administration. The specific goal of most therapy drugs nowadays is to block or interfere with the signal transduction pathways of the cancer cells. In chronic myeloid leukemia, a chromosomal translocation of chromosomes 9 and 22 may occur which would result in the fusion of the ABL gene on chromosome 9 with the BCR gene in chromosome 22 [11]. This accounts for the majority cases of CML. Studies of various oncogenes such as BCR-ABL indicate that these proteins can transform and alter cells in such a way as to prevent apoptosis (cell death) by rendering them independent of cytokines. The substrates of these proteins also play a factor in poor adhesion to neighbor cells which may also be another possible mechanism for leukemia since those cells will not stop growing even after contacting and infringing on nearby cells. Most of these oncogenes are typically composed to tyrosine kinases which can be blocked by the inhibition of single pathways. Chronic myeloid leukemia is very sensitive to many oral drugs which yield a high success rate of remissions in patients. Two of the most common drugs used in chemotherapy to treat CML are hydroxyurea and busulfan which are particular cytotoxic without generating high adverse cytogenic responses and usually do not create an effect on the transformation to the acute blast stage [12]. Chronic lymphocytic leukemia on the other hand, may not even require treatment for the disease or may require first-line or second line treatment options. First line treatment option can employ one or several combinations of alkylating agents such as chloroambucil or fludarabine with other drugs to varying effectiveness such as cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone (CHOP). Second line treatments are for patients suffering from a relapse of the disease after first-line treatments. Second-line treatments are more aggressive and may employ several antibodies particularly known to target lymphocytes such as alemtuzumab (Campath), and will require a combination of other drugs [11]. Despite the high success rates of using chemotherapy treatments for chronic leukemia patients, their quality of life is still reduced since no matter how targeted or specific the drugs are, they are still cytotoxic and will kill normal healthy cells which would result in a weakened immune system, thus a diminished quality of life.
The treatment plans for acute leukemia patients are much more aggressive and intensive since AML and ALL rapidly propagate and will be fatal in a matter of weeks if left untreated. For the specific case of acute myeloid leukemia, significant advances have been made over the years in the understanding of molecular pathways of the disease which led to the creation of more specific and targeted drug therapy. 50-75% percent of AML patients achieve complete remission but unfortunately, only 20-30% of the patients enjoy long-term disease survival while the rest die from their disease [13]. How effective the drugs in chemotherapy are depends greatly a variety of factors including the interactions between countless gene products that can influence and affect the drug toxicity and metabolism. Furthermore, specific genetic markers may also be utilized as a way to accurately classify subtypes of the diseases and lead to a more thorough approach to chemotherapy regimen and may also lead to the new drug targets that can alter the resistance of the disease [14].
The chemotherapy regimen for AML and ALL depends greatly on the subtypes of these leukemia and how resistant each one are to drug therapy. Both AML and ALL are very similar to each other with the major noticeable difference as the fact that AML typically occurs in adults while ALL typically occurs in young children. Our current understanding so far of the underlying genetic aberrations that results in the induction of ALL has a few common features even though different subtypes have a few key differences. The underlying mechanisms may include “aberrant expression of proto-oncogenes, chromosomal translocations that create fusion genes encoding active kinases and altered transcription factors, and hyperdiploidy involving more than 50 chromosomes [15].” Figure 4 contains pictographically descriptive statistics that detail the above statement. Each of these processes may alter pathways that result in the formation of nonfunctional stem cells. Specific genetic aberrations include chimeric transcription factors that can modify and alter the expression of genes that allow for the uncontrolled self-renewal of the stem cells. The TEL-AML 1 fusion gene and the MLL gene are results of translocations and they most commonly inhibit transcription pathways but are also aided by other HOX genes and HOX cofactors. This yields a potential target for specific drugs that can inhibit the signal transduction pathways of the HOX gene expression. Another type of mutation events may also contribute to and result in leukemia by itself or as a combination with the above genetic factors deals with the overexpression of the tyrosine kinase receptor called FLT-3 or the altered regulatory pathways of tumor suppressants such as the retinoblastoma protein or the p53 protein [15].
Figure 4: Estimated Frequency of the Predicted Genotypes of ALL [15]
All of these factors in the pathogenesis and prognosis of ALL result in different levels of sensitivity to chemotherapy; however, recently developed methods of gene-expression profiling help to accurately label and identify minor differences between the various subtypes of ALL which can lead to more specific and targeted drug therapy. As of now, chemotherapy for ALL focuses on the manufacture and delivery of drugs that work well with our understanding of the various genes that encode drug targets, transporters, and drug-metabolizing enzymes [15].
On the other hand, AML currently has five broad mechanisms that underlie the onset of this disease. The first of which covers all translocations that can be detected by the G-banded metaphase analysis. The second is single gene mutations that almost singlehanded cause the pathogenesis of AML. The third deals with the overexpression of genes while the fourth is underexpression of genes. Lastly, the fifth has to do with copy number alterations [16]. These are just the five underlying mechanisms commonly found as of now but more are in the progress of being discovered. Chemotherapy for AML most frequently uses two main drugs, daunorubicin and cytarabine [17], as well as a combination of other less active drugs. Typically, the dosage required depends on the patient’s age and weight and are given over a week long period [18].
Another method of leukemia treatment that recently made noteworthy advances is immunotherapy. This is possible due to a more thorough and deep understanding of the causes and mechanisms of the disease on a molecular and genetic level. The core of immunotherapy is merely to trigger a response from the host’s immune system so that the host’s body can fight off of the cancerous cells. This is easier said than done since, not unlike most cancers leukemia has a method of evading the immune system and avoiding detection and subsequent elimination. Different methods of immunotherapy are available including whole cell vaccines in which patients are injected with genetically modified autologous that are supposed to invoke an immune response. Another method is vaccines contained targeted peptides that are meant to attack known leukemia antigens [19]. Immunotherapy proves to be increasingly effective as our understanding of the disease grows.
All of the leukemia treatments discussed above are not guaranteed to generate complete remission every time; however during remission, undergoing a bone marrow transplant will highly increase the chance of enjoying a long-term disease free life-span. As with all treatments, the bone marrow transplant contains several risks and side-effects that may potentially be life-threatening. Transplants can be done using matching bone marrow from a related or unrelated donor. Typically, patients that are approved for a bone marrow transplant will have to undergo intensive chemotherapy first to destroy all traces of cancer cells. The transplant itself usually takes less than a day; however, the time it takes for the donor bone marrow to assimilate completely into the body may range from a six months period to two whole years.
There are two types of transplants, autologous bone marrow transplantation, and allogeneic bone marrow transplantation. Autologuous transplant involves using the patient’s own bone marrow; however, this transplant is risky since there is a potential for the reinfusion of tumor cells back into the patient. This procedure is generally safer for the older patients. On the other hand, allogeneic transplantation involves using bone marrow from a donor, related or unrelated. The risks of this procedure are higher the more poorly matched the host and the donor and are also unsafe for older patients. The most common complications resulting from transplant are graft-versus-host disease which affects the intestines, skin, and liver and will vary in intensity, graft rejection in which the donor bone marrow are destroyed by the host’s body, pulmonary complications which are associated with a high mortality rate, and the veno-occlusive disease of the liver which is also fatal [20]. In the end, it is up to the doctor and the patients to determine whether transplant is really the best course of action after discussing other alternative treatments and associated risks. It is the only known procedure for long-term survival in acute leukemia patients.
Conclusion
With a complex disease such as leukemia, even more complex treatment plans must be developed to combat, contain, and hopefully cure this disease. There are many options available to those who are unfortunate enough to acquire this disease and more treatment plans and options are available everyday as countless people relentlessly make significant contributions to this cause. With the continuous advancement in technology and medicines, hopefully more specific and targeted treatment regimen can be generated. Ideally, we would want to create a plan that is the most cost-effective, time-efficient, and targeted, with the least amount of pain and suffering and unwanted side-effects. However, there are many things that the common person can do to help reduce their risk of acquiring leukemia such as limiting their exposure to known carcinogenic materials and consuming products such as green tea, which are arbitrarily proven to have a connection with preventative actions of cancer [21]. In the end, it requires a cooperative effort from patients, family, physicians, and everyone connected towards the common goal of finding a humane cure for leukemia.
References
[1] Guillerman, R. P., S. D. Voss, and B. R. Parker. "Leukemia and Lymphoma." Radiologic clinics of North America 49.4 (2011): 767,97, vii. Print. DOI
[2] McKenna, Samuel J. "Leukemia." Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 89.2 (2000): 137-9. Print. DOI
[3] Kampen, Kim R. "The Discovery and Early Understanding of Leukemia." Leukemia research 36.1 (2012): 6-13. Print.DOI
[4] Rabbitts, Terence H. "Translocations, Master Genes, and Differences between the Origins of Acute and Chronic Leukemias." Cell 67.4 (1991): 641-4. Print. DOI
[5] Ludwig, Cynthia D. "Leukemia." Medsurg Nursing 18.3 (2009): 190,190, 194. Print.DOI
[6] Finch, Stuart C. "Radiation-Induced Leukemia: Lessons from History." Best Practice & Research Clinical Haematology 20.1 (2007): 109-18. Print. DOI
[7] Little, John, B. "Radiation Carcinogenesis." Life Sciences & Medicine Carcinogenesis 21.3 (1999): 397--404. Print. DOI
[8] Virgin, Herbert W., E. John Wherry, and Rafi Ahmed. "Redefining Chronic Viral Infection." Cell138.1 (2009): 30-50. Print.DOI
[9] Proietti, Fernando A., et al. "Global Epidemiology of HTLV-I Infection and Associated Diseases." Oncogene24.39 (2005): 6058-68. Print.DOI
[10] Benson, Kathleen F., and Marshall Horwitz. "Familial Leukemia." Best Practice & Research Clinical Haematology 19.2 (2006): 269-79. Print.DOI
[11] Enright, Helen, and Jonathan Bond. "Chronic Leukemias." Disease-a-Month 54.4 (2008): 242-55. Print. DOI
[12] Sawyers, Charles L. "Chronic Myeloid Leukemia." The New England journal of medicine 340.17 (1999): 1330-40. Print. DOI
[13] Tallman, Martin S, D. Gary Gilliland, and Jacob M. Rowe. "Drug Therapy for Acute Myeloid Leukemia." REVIEWS IN TRANSLATIONAL HEMATOLOGY 106.4 (2005): 1154--1163. Print. DOI
[14] Cheok, Meyling H., and Christophe Roumier. "Pharmacogenomics in Acute Myeloid Leukemia." Pharmacogenomics 10 (2009): 1839+. Print. DOI
[15] Pui,Ching-Hon, Mary V. Relling, and James R. Downing. "MECHANISMS OF DISEASE: Acute Lymphoblastic Leukemia." The New England journal of medicine 350.15 (2004): 1535-48. Print. DOI
[16] Bagg, Adam, and Christopher D. Watt. "Molecular Diagnosis of Acute Myeloid Leukemia." Expert Review of Molecular Diagnostics 10 (2010): 993+. Print. DOI
[17] Lowenberg, Bob, James R. Downing, and Alan Burnett. "Acute Myeloid Leukemia." N Engl J Med 341.14 (1999): 1051-62. Print. DOI
[18] Phillips, G. L., et al. "High-Dose Cytarabine and Daunorubicin Induction and Postremission Chemotherapy for the Treatment of Acute Myelogenous Leukemia in Adults." Blood 77.7 (1991): 1429-35. Print. DOI
[19] Guinn, Barbara-Ann, et al. "Immunotherapy of Myeloid Leukaemia." Immunotherapy 56.7 (2007): 943--957. Print. DOI
[20]Armitage, James O. "Bone Marrow Transplantation." N Engl J Med 330.12 (1994): 827-38. Print. DOI [21]Yang, Chung S., et al. "Tea and Tea Polyphenols in Cancer Prevention." The Journal of nutrition 130.2S (2000): S472-478S. Print. DOI
Current Comprehensive Treatments of Leukemia
Mi Kieu Bui
Drexel Undergraduate
December, 8, 2012
Abstract
Leukemia is a broad class of blood cancer that can be further categorized into four major classes, each with their own subtypes based on a number of morphological and cytological differences. There is no exact cause of leukemia but some people have a higher risk for the development of the disease than others due to a complex combination of many factors that may be environmentally or genetically based. Leukemia was first described over 200 years ago but it was not until less than 100 years ago that any significant advances or methods of treatments are formed. Leukemia, while not exactly curable, can be treated in a number of different ways. All of these treatment options have their own advantages and disadvantages and are usually specific to each patient depending on many individual characteristics of the patients and the disease.
Introduction
Leukemia is a class of blood cancer that results from a characteristic overabundance of white blood cells. Not to be confused with lymphoma, which contains white blood cells generated by the lymphoid immune system; leukemia generally refers to the white blood cells generated by the bone marrow [1]. In standard leukemia, blood white cells, either myelocytes or lymphocytes, rapidly and uncontrollably proliferate and accumulate in the blood stream which generates an overabundance of the white blood cells and suppresses the production of other components of blood such as red blood cells, platelets, and various antibodies; this results in a weakened immune system. The suppression is what resulted in symptoms commonly associated with leukemia patients such as fatigue, shortness of breath, fever, chills, migraines, bone or joint pain, excessive bleeding and bruising, and infections [2]. Left untreated, leukemia commonly results in death, with differing life expectancies depending on the subtype of leukemia. Leukemia is divided into four major subtypes which can also be further differentiated based on genetic aberrations. The four major subtypes of leukemia are distinguished based on a number of morphological differences that concern the type of white blood cells affected and their maturation stages. The four subtypes are chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and acute lymphocytic leukemia (ALL) [3]. Myeloid (or myelogenous) and lymphocytic leukemia refer to the cell types in which this disorder develop and acute or chronic are classified based on the maturity of these cells. In chronic leukemia, the cells are mature and thus divide more slowly than its acute counterpart, which refers to young white blood cells called blasts which divide much more frequently. Acute leukemia frequently occurs quite suddenly while chronic has a slower onset. Acute leukemia, with the exception of AML, is more commonly diagnosed in young children while older patients typically suffer from chronic leukemia [4].
Causes and Risk Factors
There are no truly known causes and risk factors for most types of leukemia; however, there are suspected risk factors. Risk factors can include exposure to radiation, exposure to carcinogenic chemicals, viral infections, genetic predisposition, or chromosomal abnormality such as Down syndrome [5].
When various types of radiation were first discovered before the start of the 19th century by numerous people, including Rutherford, Edison, and others, it became a frequent and flippant method of commercial use and diagnostic processes. Radium or thorium based products were released over-the-counter and consumed by the general public, many physicians used radiation therapy as an attempted method to cure diseases, and many of the general public employed flippant use of x-rays for pointless entertainment. It was not until years later and many linked cases of leukemia and various other cancers arising from people with high levels of exposure to radiation that the dangers of radiation were truly known or accepted. Other information supporting the fact that radiation is linked to leukemia came from atomic bomb survivors from the Japan detonation of the atomic bombs and from workers in the area after the events. More studies that supports the danger of radiation came from workers with inadequate protective equipments in nuclear power plants [6].
Radiation induces leukemia or other cancer by directly damaging the DNA through two possible mechanisms. The first of which is the direct ionization of water which produces highly reactive radicals and the second mechanism is the direct damage to DNA caused by outer shell electrons that are knocked off during radiation exposure. Both of these mechanisms can cause single-strand breaks or double-strand breaks in the DNA which may result in unstable chromosomes and lead to various mutations. Some chromosomal rearrangements may activate certain protooncogenes that can lead to the development of leukemia. Any mutation that occurs in a cell is most likely to transfer into its entire offspring as shown in Figure 1. There is a linear relationship between the dosage of radiation and the number of mutations that arises as shown in Figure 2, indicating that higher level of radiation exposure lead to a higher risk of leukemia. However, other factors and phenomena may complicate the understanding of radiation induced leukemia [6].
Leukemia can also be caused by viral infections such as by the HTLV-I (human T-lymphotropic virus type I. Viruses generally infect cells by entering the host’s cellular environment and injecting viral DNA or RNA, which typically alters the host’s own mechanisms into a viral production industry. For effective infections, there has to be a balance between the host immunity and viral virulence since it is not advantageous to have the virus or the host killed too soon. How this actually occurs is still unclear in immunobiology [8]. As shown in Figure 3, there are various points that can lead to what constitutes as an acute or chronic infection as well as for maintaining the infection. In the case of the HTLV-I infection, the virus may be transmitted through sexual intercourse, from mother to child via breast-feeding, or via intravenous exposure to blood [9].
HTLV-1 is linked to the development of ATL (Adult T-cell Leukemia) which may occur when the virus infect lymphocytes in the bone marrow [9].
The risk for leukemia can also be caused by genetic predisposition which occurred since specific mutations can be inherited in a Mendelian fashion which may manifest in a favorable environment. Some studies show that leukemia can be caused by random sporadic mutations; however, there is increasing evidence that the risk for leukemia runs in family based on a variety of studies. The search for a single chromosome or gene that indicates a high risk for leukemia is still futile; however, several locations on the genome have been identified as most likely. CLL is most commonly found to be inherited and appears to be located on a single gene that is based on the typical autosomal dominant inheritance. With various complications of expressed phenotypes and environmental conditions, it is difficult to localize the exact location on the chromosome. AML on the other hand, is also shown to be frequently a familiar predisposition which may be inherited from a form of platelet disorder and is found to most frequently occur in patients with a certain mutated protein [10].
Other risks of leukemia associated with inherited genetic disorders are in patients with Down Syndrome and bone marrow failure syndromes [10]. Notice that patients diagnosed with these chromosomal disorders are not guaranteed to develop leukemia but are merely at a higher risk of developing leukemia.
History of Early Treatments
The first known case of leukemia was discovered by Peter Cullen in the early 1800s when he examined a patient and noticed the appearance of a milky serum in the blood. The next few cases of leukemia have differing symptoms but similar appearances in the composition of blood. It was not until 1845 that the name leukemia, meaning white blood in Greek, was coined by John Hughes Bennett. After many years of various contributions by different physicians, the disease was finally connected to the bone marrow in the late 1800s [3].
When leukemia was first described, treatment options were not exactly available and acting physicians back then tended to treat patients based on their displayed symptoms. The most common treatment was blood-letting in which patients seemed to recover but it was not documented as to how long they survived after the treatment. It was not until more than 100 years later that any alternative treatment options were created. The first of which were iron supplements in the 1930s which only appeared to work because it treated the anemia symptoms commonly associated with not having enough oxygen carried by the red blood cells. After that, various radiation techniques were used including exposure to radioactive compounds or administration of electromagnetic rays [3]. These techniques may merely kill the cancerous cells at the moment but they also harmed the body to a significant degree and caused a higher risk for the reoccurrences of leukemia or other types of cancer.
Current Treatments
Roughly 200 years after leukemia was first documented, treatment options have significantly improved by leaps and bounds to the point that cures are actually available for certain types of leukemia. Current options for treatment are chemotherapy, immunotherapy, radiation therapy, and transplant. Each of these treatment options has their own advantages and disadvantages and the treatment plan utilized for each patient is unique and may involve one or a combination these options. The treatment plans for patients are generated with the types and subtypes of leukemia, age, health issues, and various other criteria and factors in mind. Most leukemia are initially diagnosed via a bone marrow biopsy which lead to very specific classifications of the subtypes of the disease.
Chemotherapy drugs can be administered orally or by injection into the veins. The goal of chemotherapy or drug therapy is to kill the cancerous cells and hopefully induce remission. However, the general problem with this is that it is quite difficult to synthesize drugs that are specific enough to attack and kill the leukemia cells without harming the body’s own regular functioning cells. Added to this complication is the fact that not enough is actually understood regarding the mechanism of leukemia and how to differ between normal and abnormal white blood cells. Another complication is the developing drug resistance that the cancerous cells seemed to adopt as they adapt to various drugs.
For the chronic subtypes of leukemia, the drug therapy is not as intensive as the acute types because chronic leukemia develop much more slowly and can usually be controlled by periodic drug administration. The specific goal of most therapy drugs nowadays is to block or interfere with the signal transduction pathways of the cancer cells. In chronic myeloid leukemia, a chromosomal translocation of chromosomes 9 and 22 may occur which would result in the fusion of the ABL gene on chromosome 9 with the BCR gene in chromosome 22 [11]. This accounts for the majority cases of CML. Studies of various oncogenes such as BCR-ABL indicate that these proteins can transform and alter cells in such a way as to prevent apoptosis (cell death) by rendering them independent of cytokines. The substrates of these proteins also play a factor in poor adhesion to neighbor cells which may also be another possible mechanism for leukemia since those cells will not stop growing even after contacting and infringing on nearby cells. Most of these oncogenes are typically composed to tyrosine kinases which can be blocked by the inhibition of single pathways. Chronic myeloid leukemia is very sensitive to many oral drugs which yield a high success rate of remissions in patients. Two of the most common drugs used in chemotherapy to treat CML are hydroxyurea and busulfan which are particular cytotoxic without generating high adverse cytogenic responses and usually do not create an effect on the transformation to the acute blast stage [12]. Chronic lymphocytic leukemia on the other hand, may not even require treatment for the disease or may require first-line or second line treatment options. First line treatment option can employ one or several combinations of alkylating agents such as chloroambucil or fludarabine with other drugs to varying effectiveness such as cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone (CHOP). Second line treatments are for patients suffering from a relapse of the disease after first-line treatments. Second-line treatments are more aggressive and may employ several antibodies particularly known to target lymphocytes such as alemtuzumab (Campath), and will require a combination of other drugs [11]. Despite the high success rates of using chemotherapy treatments for chronic leukemia patients, their quality of life is still reduced since no matter how targeted or specific the drugs are, they are still cytotoxic and will kill normal healthy cells which would result in a weakened immune system, thus a diminished quality of life.
The treatment plans for acute leukemia patients are much more aggressive and intensive since AML and ALL rapidly propagate and will be fatal in a matter of weeks if left untreated. For the specific case of acute myeloid leukemia, significant advances have been made over the years in the understanding of molecular pathways of the disease which led to the creation of more specific and targeted drug therapy. 50-75% percent of AML patients achieve complete remission but unfortunately, only 20-30% of the patients enjoy long-term disease survival while the rest die from their disease [13]. How effective the drugs in chemotherapy are depends greatly a variety of factors including the interactions between countless gene products that can influence and affect the drug toxicity and metabolism. Furthermore, specific genetic markers may also be utilized as a way to accurately classify subtypes of the diseases and lead to a more thorough approach to chemotherapy regimen and may also lead to the new drug targets that can alter the resistance of the disease [14].
The chemotherapy regimen for AML and ALL depends greatly on the subtypes of these leukemia and how resistant each one are to drug therapy. Both AML and ALL are very similar to each other with the major noticeable difference as the fact that AML typically occurs in adults while ALL typically occurs in young children. Our current understanding so far of the underlying genetic aberrations that results in the induction of ALL has a few common features even though different subtypes have a few key differences. The underlying mechanisms may include “aberrant expression of proto-oncogenes, chromosomal translocations that create fusion genes encoding active kinases and altered transcription factors, and hyperdiploidy involving more than 50 chromosomes [15].” Figure 4 contains pictographically descriptive statistics that detail the above statement. Each of these processes may alter pathways that result in the formation of nonfunctional stem cells. Specific genetic aberrations include chimeric transcription factors that can modify and alter the expression of genes that allow for the uncontrolled self-renewal of the stem cells. The TEL-AML 1 fusion gene and the MLL gene are results of translocations and they most commonly inhibit transcription pathways but are also aided by other HOX genes and HOX cofactors. This yields a potential target for specific drugs that can inhibit the signal transduction pathways of the HOX gene expression. Another type of mutation events may also contribute to and result in leukemia by itself or as a combination with the above genetic factors deals with the overexpression of the tyrosine kinase receptor called FLT-3 or the altered regulatory pathways of tumor suppressants such as the retinoblastoma protein or the p53 protein [15].
Figure 4: Estimated Frequency of the Predicted Genotypes of ALL [15]
All of these factors in the pathogenesis and prognosis of ALL result in different levels of sensitivity to chemotherapy; however, recently developed methods of gene-expression profiling help to accurately label and identify minor differences between the various subtypes of ALL which can lead to more specific and targeted drug therapy. As of now, chemotherapy for ALL focuses on the manufacture and delivery of drugs that work well with our understanding of the various genes that encode drug targets, transporters, and drug-metabolizing enzymes [15].
On the other hand, AML currently has five broad mechanisms that underlie the onset of this disease. The first of which covers all translocations that can be detected by the G-banded metaphase analysis. The second is single gene mutations that almost singlehanded cause the pathogenesis of AML. The third deals with the overexpression of genes while the fourth is underexpression of genes. Lastly, the fifth has to do with copy number alterations [16]. These are just the five underlying mechanisms commonly found as of now but more are in the progress of being discovered. Chemotherapy for AML most frequently uses two main drugs, daunorubicin and cytarabine [17], as well as a combination of other less active drugs. Typically, the dosage required depends on the patient’s age and weight and are given over a week long period [18].
Another method of leukemia treatment that recently made noteworthy advances is immunotherapy. This is possible due to a more thorough and deep understanding of the causes and mechanisms of the disease on a molecular and genetic level. The core of immunotherapy is merely to trigger a response from the host’s immune system so that the host’s body can fight off of the cancerous cells. This is easier said than done since, not unlike most cancers leukemia has a method of evading the immune system and avoiding detection and subsequent elimination. Different methods of immunotherapy are available including whole cell vaccines in which patients are injected with genetically modified autologous that are supposed to invoke an immune response. Another method is vaccines contained targeted peptides that are meant to attack known leukemia antigens [19]. Immunotherapy proves to be increasingly effective as our understanding of the disease grows.
All of the leukemia treatments discussed above are not guaranteed to generate complete remission every time; however during remission, undergoing a bone marrow transplant will highly increase the chance of enjoying a long-term disease free life-span. As with all treatments, the bone marrow transplant contains several risks and side-effects that may potentially be life-threatening. Transplants can be done using matching bone marrow from a related or unrelated donor. Typically, patients that are approved for a bone marrow transplant will have to undergo intensive chemotherapy first to destroy all traces of cancer cells. The transplant itself usually takes less than a day; however, the time it takes for the donor bone marrow to assimilate completely into the body may range from a six months period to two whole years.
There are two types of transplants, autologous bone marrow transplantation, and allogeneic bone marrow transplantation. Autologuous transplant involves using the patient’s own bone marrow; however, this transplant is risky since there is a potential for the reinfusion of tumor cells back into the patient. This procedure is generally safer for the older patients. On the other hand, allogeneic transplantation involves using bone marrow from a donor, related or unrelated. The risks of this procedure are higher the more poorly matched the host and the donor and are also unsafe for older patients. The most common complications resulting from transplant are graft-versus-host disease which affects the intestines, skin, and liver and will vary in intensity, graft rejection in which the donor bone marrow are destroyed by the host’s body, pulmonary complications which are associated with a high mortality rate, and the veno-occlusive disease of the liver which is also fatal [20]. In the end, it is up to the doctor and the patients to determine whether transplant is really the best course of action after discussing other alternative treatments and associated risks. It is the only known procedure for long-term survival in acute leukemia patients.
Conclusion
With a complex disease such as leukemia, even more complex treatment plans must be developed to combat, contain, and hopefully cure this disease. There are many options available to those who are unfortunate enough to acquire this disease and more treatment plans and options are available everyday as countless people relentlessly make significant contributions to this cause. With the continuous advancement in technology and medicines, hopefully more specific and targeted treatment regimen can be generated. Ideally, we would want to create a plan that is the most cost-effective, time-efficient, and targeted, with the least amount of pain and suffering and unwanted side-effects. However, there are many things that the common person can do to help reduce their risk of acquiring leukemia such as limiting their exposure to known carcinogenic materials and consuming products such as green tea, which are arbitrarily proven to have a connection with preventative actions of cancer [21]. In the end, it requires a cooperative effort from patients, family, physicians, and everyone connected towards the common goal of finding a humane cure for leukemia.
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